Cell-specific expression of transforming growth factor-beta in rat liver. Evidence for autocrine regulation of hepatocyte proliferation.

Abstract

Expression of the group of cytokines known as transforming growth factor-beta (TGF-beta 1, -beta 2 and -beta 3) is increased during liver regeneration induced by a 70% partial hepatectomy. The origin of these changes was examined in purified isolates of hepatocytes, sinusoidal endothelial cells, Kupffer cells (liver macrophages), and lipocytes (Ito or stellate cells) from normal and regenerating liver. In normal liver, TGF-beta 1 and -beta 2 levels were relatively high in sinusoidal endothelial cells and Kupffer cells. After partial hepatectomy, an early peak of TGF-beta 2 and -beta 3 was present in all four cell types, followed by a sustained increase in mRNA for TGF-beta 1, -beta 2, and -beta 3 primarily in the hepatocyte population. The specificity of these changes was established by examining a mechanistically different injury model, fibrosis induced by ligation of the biliary duct. In this model, TGF beta mRNA was increased only in lipocytes and the increase was progressive over a 7-d period of observation. Secretion of TGF beta protein was examined in cell isolates placed in short-term primary culture and generally reflected the corresponding mRNA level. The TGF beta released by hepatocytes was entirely in the latent form, whereas the individual nonparenchymal cell isolates released 50-90% active TGF beta. Hepatocyte-conditioned culture medium, after treatment to activate latent TGF beta, inhibited hepatocellular DNA synthesis as did the authentic factor. The data indicate that after injury TGF beta increases selectively in the cells that are the target of the factor, i.e., in hepatocytes after partial hepatectomy and in lipocytes in inflammation and fibrosis. We conclude that the effects of TGF beta in liver regeneration and fibrogenesis are predominantly, if not exclusively, autocrine.